title: Identification of a novel non-retinoid pan inverse agonist of the retinoic acid receptors.
abstract: Retinoids are potent forms of vitamin A and are involved in a broad range of physiological processes and the pharmacological effects of retinoids are primarily mediated by the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Several natural and synthetic RAR modulators have proven to be clinically useful for a number of therapeutic indications including cancer, psoriasis, and diabetes. Unfortunately, these agents lead to a number of significant side effects. Most synthetic retinoid ligands are based on the retinoid scaffold and thus have similarities to the natural ligand with all previously disclosed RAR ligands having a carboxylic acid that makes a critical ionic bridge within the ligand binding domain of the receptors. The potential therapeutic value offered from RAR modulation provides the impetus to identify novel ligands based on unique scaffolds that may offer improved toxicity and pharmacokinetic profiles. Here we describe the identification of an atypical RAR inverse agonist that represents the first non-acid, non-retinoid direct modulator of RAR receptor subfamily. SR-0065 functions as a pan-RAR inverse agonist suppressing the basal activity of RARα, RARβ, and RARγ, as well as inhibiting agonist-induced RAR activity. SR-0065 treatment enhanced receptor interaction with a peptide representative of the corepressor SMRT, and in cells SR-0065 enhances recruitment of SMRT to the promoter of the RARγ dependent gene, Cyp26A1. The acid form of SR-0065, SR-1758, was inactive in all assays. Thus, SR-0065 represents a new class of non-acid, non-retinoid RAR modulator that may be used as a point to initiate development of improved RAR-targeted drugs.
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, United States.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Busby
authors.forename: Naresh
authors.initials: N
authors.lastname: Kumar
authors.forename: Dana S
authors.initials: DS
authors.lastname: Kuruvilla
authors.forename: Monica A
authors.initials: MA
authors.lastname: Istrate
authors.forename: Juliana J
authors.initials: JJ
authors.lastname: Conkright
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Wang
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cameron
authors.forename: William R
authors.initials: WR
authors.lastname: Roush
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Burris
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
mesh_terms: D000818:Animals; D002460:Cell Line; D004146:Dioxanes / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*; D018168:Receptors, Retinoic Acid / Q000819:agonists*; D047488:Retinoid X Receptors / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D004146:Dioxanes; D008024:Ligands; D015363:Quinolones; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; C570595:SR-0065